VOCABULARY

RNA: ribonucleic acid, which is present in all living cells, acts as a messenger carrying DNA instructions.

Genes: sections of DNA, which make RNA, which then make proteins, which come together to form a protein complex.

nBAF: the protein complex necessary for long-term memory.

baf53b: a protein within nBAF.

Chromatin: the combination of genomic DNA and histone proteins, which resides in the nucleus of a cell.

Nucleosome: the repeating unit of chromatin, which is a length of DNA (146 base pairs) wrapped around a ball of histone proteins. When viewed through a microscope, it looks like beads on a string.

Nucleosome remodeling: when nBAF attaches to chromatin and physically moves nucleosomes away, allowing a gene to be turned on.

Epigenetics: Changes in gene expression caused by mechanisms other than changes to their underlying DNA sequence.

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UC Irvine neurobiologists have discovered a protein complex in neurons that is essential to long-term memory formation and is also corrupted in the brains of people with some developmental disabilities such as autism.

This complex is corrupted by the mutation of a specific protein molecule, and replacing that mutated molecule in laboratory mice restores their long-term memory – suggesting a possible gene therapy for humans, the researchers reported.

Protein complexes access genes – portions of DNA – and turn them on and off at the right time to enable neurons in the brain to work properly, said Marcelo Wood, associate professor at UCI's Center for the Neurobiology of Learning and Memory and director of the Interdepartmental Neuroscience Program.

Wood's lab has identified nBAF as the protein complex needed for long-term memory. nBAF is found only in neurons. When nBAF is corrupted by a mutation of its gene-encoding molecule baf53b, it can no longer perform the role of "nucleosome remodeling," the means by which nBAF accesses genes.

When UCI researchers replace mutated baf53b with non-mutated baf53b in laboratory mice, it leads to a functioning, gene-accessing nBAF protein complex and results in the return of their long-term memory, Wood said.

This research furthers the science of epigenetics, which has to do with gene access and gene function without a change to DNA coding. Cognitive impairments in learning and memory and neurodevelopmental disorders once thought to be genetic may be epigenetic.

ACCESSING DNA

If you unraveled all of the chromosomes in just one cell and lined them up, there would be six feet of DNA, which determines what traits we inherit. DNA resides in the microscopic nucleus of a cell and is packed in chromatin. Chromatin is made of repeating units of nucleosomes, a specific length of DNA wrapped around balls of proteins called histones.

When viewed through a microscope, chromatin looks like beads on a string (see bottom of infographic on Page 1). DNA must be wrapped around nucleosomes so that it can be compacted about 10,000 times to fit in a cell's nucleus.

Accessing genes in the face of that compaction becomes a physical problem. If genes can't be accessed, they can't get turned on.

The nBAF protein complex, necessary for memory, attaches to chromatin and physically unravels the nucleosomes, allowing for a gene to be turned on and off. That action is called "nucleosome remodeling."

If the nucleosome remodeling mechanism of nBAF fails due to a mutation of baf53b, it can result in severe cognitive and neurodevelopment disorders, Wood said.

EPIGENETICS

Nucleosome remodeling plays a major role in gene function and could also play a role in disorders and diseases such as cancer, obesity, depression and addiction, Wood said.

The emerging field of epigenetics – changes to the expression of genes without any changes in their underlying DNA coding – suggests that the environment and the things we're exposed to can alter our gene function without changing our genetics.

Marcelo Wood shows the window that explains the design of experiments to understand the epigenetic mechanisms of learning and memory. STEVEN GEORGES, FOR THE REGISTER
Dr. Dina Matheos, project scientist in the Wood lab at UC Irvine's Center for the Neurobiology of Learning and Memory, prepares samples from neurons for gene expression analysis as she runs experiments aimed at understanding how gene expression occurs normally and in a disease state. STEVEN GEORGES, FOR THE REGISTER
Annie Vogel-Ciernia, a graduate student in the Department of neurobiology and Behavior at UC Irvine, uses a microscope with a video camera attached to display the types and shapes of connections (synapses) between neurons in a mouse brain. STEVEN GEORGES, FOR THE REGISTER
Marcelo Wood with research lab members, from left, project scientist Dina Matheos, graduate student Annie Vogel-Ciernia and lab technician Richard Dang. STEVEN GEORGES, FOR THE REGISTER
Marcelo Wood FOR THE REGISTER

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